Fenamiphos Proposed AEGL Document

ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR FENAMIPHOS CAS Reg. No. 22224-92-6

PROPOSED

FENAMIPHOS PROPOSED: November 2009

1 2 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 3 FOR 4 FENAMIPHOS 5 (CAS Reg. No. 22224-92-6) 6 7 8 9 10 PROPOSED 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

2 FENAMIPHOS PROPOSED: November 2009

1 2 3 PREFACE 4 5 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 6 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 7 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 8 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 9 chemicals. 10 11 AEGLs represent threshold exposure limits for the general public and are applicable to 12 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 13 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 14 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 15 The three AEGLs are defined as follows: 16 17 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 18 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 19 population, including susceptible individuals, could experience notable discomfort, irritation, or 20 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 21 transient and reversible upon cessation of exposure. 22 23 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 24 which it is predicted that the general population, including susceptible individuals, could 25 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 26 to escape. 27 28 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 29 which it is predicted that the general population, including susceptible individuals, could 30 experience life-threatening health effects or death. 31 32 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 33 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 34 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 35 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 36 of effects described for each corresponding AEGL. Although the AEGL values represent 37 threshold levels for the general public, including susceptible subpopulations, such as infants, 38 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 39 individuals, subject to unique or idiosyncratic responses, could experience the effects described 40 at concentrations below the corresponding AEGL 41 42 43

3 FENAMIPHOS PROPOSED: November 2009

1 TABLE OF CONTENTS

2 PREFACE ...... 3

3 LIST OF TABLES ...... 6

4 EXECUTIVE SUMMARY ...... 7

5 1. INTRODUCTION ...... 9

6 2. HUMAN TOXICITY DATA ...... 9 7 2.1. Acute Lethality ...... 9 8 2.2. Nonlethal Toxicity ...... 10 9 2.2.1. Odor Threshold/Odor Awareness ...... 10 10 2.2.2. Case Reports ...... 10 11 2.2.3. Exposure Studies ...... 10 12 2.3. Neurotoxicity ...... 10 13 2.4. Developmental/Reproductive Toxicity ...... 10 14 2.5. Genotoxicity ...... 10 15 2.6. Carcinogenicity ...... 10 16 2.7. Summary ...... 10

17 3. ANIMAL TOXICITY DATA ...... 10 18 3.1. Acute Lethality ...... 10 19 3.1.1. Rats ...... 11 20 3.2. Nonlethal Toxicity ...... 12 21 3.2.1. Rats ...... 12 22 3.3. Developmental/Reproductive Toxicity ...... 13 23 3.4. Genotoxicity ...... 14 24 3.5. Chronic Toxicity/Carcinogenicity...... 14 25 3.6. Summary ...... 14

26 4. SPECIAL CONSIDERATIONS ...... 15 27 4.1. Metabolism and Disposition ...... 15 28 4.2. Mechanism of Toxicity ...... 16 29 4.3. Structure Activity Relationships ...... 16 30 4.4. Other Relevant Information ...... 17 31 4.4.1. Species Variability ...... 17 32 4.4.2. Susceptible Populations ...... 17 33 4.4.3. Concentration-Exposure Duration Relationship ...... 17 34 4.4.4. Concurrent Exposure Issues ...... 17

35 5. DATA ANALYSIS FOR AEGL-1 ...... 18 36 5.1. Summary of Human Data Relevant to AEGL-1 ...... 18 37 5.2. Summary of Animal Data Relevant to AEGL-1 ...... 18 38 5.3. Derivation of AEGL-1 ...... 18

39 6. DATA ANALYSIS FOR AEGL-2 ...... 18 40 6.1. Summary of Human Data Relevant to AEGL-2 ...... 18 41 6.2. Summary of Animal Data Relevant to AEGL-2 ...... 18 42 6.3. Derivation of AEGL-2 ...... 18 4 FENAMIPHOS PROPOSED: November 2009

1 7. DATA ANALYSIS FOR AEGL-3 ...... 19 2 7.1. Summary of Human Data Relevant to AEGL-3 ...... 19 3 7.2. Summary of Animal Data Relevant to AEGL-3 ...... 19 4 7.3. Derivation of AEGL-3 ...... 19

5 8. SUMMARY OF AEGLS ...... 20 6 8.1. AEGL Values and Toxicity Endpoints ...... 20 7 8.2. Comparison with Other Standards and Guidelines ...... 20 8 8.3. Data Adequacy and Research ...... 21

9 9. REFERENCES ...... 22

10 APPENDIX A: DERIVATION OF AEGL VALUES ...... 26

11 APPENDIX B: TIME-SCALING CALCULATIONS ...... 29

12 APPENDIX C: DERIVATION SUMMARY FOR FENAMIPHOS AEGLS ...... 31

13 APPENDIX D: CATEGORY PLOT FOR FENAMIPHOS ...... 34

14 APPENDIX E: BENCHMARK EXPOSURE CALCULATIONS ...... 37 15 16

5 FENAMIPHOS PROPOSED: November 2009

1 LIST OF TABLES 2 3 TABLE 1. Summary of AEGL Values for Fenamiphos ...... 8 4 TABLE 2. Chemical and Physical Properties ...... 9 5 TABLE 3. Summary of Acute Inhalation Data for Fenamiphos in Laboratory Animals ...... 12 6 TABLE 4. AEGL-1 Values for Fenamiphos ...... 18 7 TABLE 5. AEGL-2 Values for Fenamiphos ...... 19 8 TABLE 6. AEGL-3 Values for Fenamiphos ...... 20 9 TABLE 7. Summary of AEGL Values ...... 20 10 TABLE 8. Extant Standards and Guidelines for Fenamiphos ...... 21 11 12

6 FENAMIPHOS PROPOSED: November 2009

1 EXECUTIVE SUMMARY 2 3 Fenamiphos is an organophosphate nematicide and insecticide that is used to control a 4 variety of nematodes, thrips, aphids, beetles, root weevils, and corn borers. It was first registered 5 in 1972 for use on annual field and vegetable crops or on established perennial, deciduous, and 6 tropical fruit crops. In the U.S., the registrant cancelled use and formulation for use of all of its 7 existing fenamiphos registrations in areas with predominantly sand or loamy sand, hydrologic 8 soil group A soils that are excessively drained, and shallow water tables effective May 31, 2005. 9 Registrations were cancelled for use on all other soils in the U.S. effective May 31, 2007. Prior 10 to cancellation, annual domestic use for the United States was approximately 780,000 pounds of 11 active ingredient. The U.S. EPA has tolerances for crops on which fenamiphos is used and for 12 food commodities imported into the U.S. 13 14 Fenamiphos is readily absorbed through the skin and numerous studies are available 15 describing the pharmacokinetics and toxicity after topical application. Dermal exposure may 16 increase the total absorbed dose when it occurs with oral or inhalation exposure. However, 17 because the dermal route is not relevant to the inhalation route of exposure, the data on dermal 18 exposure were not analyzed with regard to developing AEGL values for fenamiphos. Relative to 19 occupational dermal and oral exposure, inhalation is a minor exposure route and this is reflected 20 in the paucity of inhalation toxicity data. No quantitative data are available regarding the 21 inhalation toxicity of fenamiphos in humans. 22 23 No AEGL-1 values were established because the AEGL-1 values would have been too close 24 to or exceeded AEGL-2 values. 25 26 The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of 27 experimental data and the steep exposure-response relationship justify estimating AEGL-2 28 values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5% 29 mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 mg/m3; and 60% mortality 30 at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by 31 Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died 32 after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70% 33 mortality at 145 mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour 34 study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100% 35 mortality at 155 mg/m3, and female rats experienced 50% mortality at 100 mg/m3; 90% mortality 36 at 155 mg/m3; and 100% mortality at 191 mg/m3. 37 3 38 The AEGL-3 was derived using the 4-hour BMCL05 of 46.6337 mg/m for lethality of 39 fenamiphos in female rats (Thyssen 1979a). This is considered a threshold for lethality for 40 fenamiphos and is the most conservative benchmark value calculated from the test animals used 41 in the study. Lethality data were sufficient for empirical derivation of a time-scaling factor (n) 42 for use in the equation Cn x t = k. The value of n was 4.8 and was used to time scale AEGL 43 values. The mechanism of action of organophosphate anticholinesterases is well understood; 44 their activity on cholinergic systems is the same across species. Variability in response is 45 primarily a function of varying cholinesterase activity level and types of cholinesterase. Humans 46 have greater levels of plasma cholinesterase than do other species which allows for greater 47 binding of anticholinesterase compounds such as fenamiphos, thereby decreasing the availability 48 of the compound to brain cholinesterase. Therefore, the interspecies uncertainty factor is limited 49 to 3. The documented variability in sensitivity among different age groups and genders, and the 7 FENAMIPHOS PROPOSED: November 2009

1 known genetic polymorphisms in A-esterases justify retention of the intraspecies uncertainty 2 factor of 10. The uncertainty factor application and rationale are the same as those applied in the 3 derivation of AEGLs for other organophosphate anticholinesterases (NRC 2003). 4 TABLE 1. Summary of AEGL Values for Fenamiphos Classification 10-minute 30-minute 1-hour 4-hour 8-hour Endpoint (Reference) AEGLB1 Not recommended due to NR NR NR NR NR (Nondisabling) exceeding AEGL-2 values Derived by 3-fold AEGLB2 reduction of the AEGL-3 1.0 mg/m3 0.80 mg/m3 0.70 mg/m3 0.53 mg/m3 0.43 mg/m3 (Disabling) values (NRC 2001; Thyssen 1979a) Derived based upon a 4-hr AEGLB3 3.0 mg/m3 2.4 mg/m3 2.1 mg/m3 1.6 mg/m3 1.3 mg/m3 BMCL of 46.6337 mg/m3 (Lethal) 05 in rats (Thyssen 1979a) 5 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 6 7 References 8 9 Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active ingredient on rats. 10 Unpublished report. Bayer AG, Wuppertal, Germany. 11 12 NRC (National Research Council). 2001. Standing operating procedures for developing acute exposure 13 guideline levels for hazardous chemicals. Committee on Toxicology, Board on Toxicology and 14 Environmental Health Hazards, Commission on Life Sciences, National Research Council. National 15 Academy Press, Washington, DC. 16 17 NRC (National Research Council). 2003. Acute Exposure Guideline Levels for Selected Airborne 18 Contaminants: Nerve agents GA, GB, GD, GF, and VX. Vol. 3. Committee on Toxicology, Board on 19 Toxicology and Environmental Health Hazards, Commission on Life Sciences, National Research 20 Council. National Academy Press, Washington, DC.

21 Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no. 22 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany. 23

8 FENAMIPHOS PROPOSED: November 2009

1 2 1. INTRODUCTION 3 4 Fenamiphos is an organophosphate nematicide and insecticide that is used to control a 5 variety of nematodes, thrips, aphids, beetles, root weevils, and corn borers. Fenamiphos is 6 manufactured by reacting 4-methyl-m-creosol with ethylisopropylamido-phosphorochloride or 7 by condensing 4-methylthio-m-cresol with O-ethyl N-isopropyl phosphoramidochloride. It was 8 first registered in 1972 for use in plant control of nematodes on annual field and vegetable crops 9 or on established perennial, deciduous, and tropical fruit crops. In the U.S., the manufacturer 10 agreed to cancel use, and formulation for use, of all of its existing fenamiphos registrations in the 11 U.S. in areas with predominantly sand or loamy sand, hydrologic soil group A soils that are 12 excessively drained, and shallow water tables effective May 31, 2005. Registrations were 13 cancelled for use on all other soils in the U.S. effective May 31, 2007. Prior to cancellation, the 14 annual domestic use for the United States was approximately 780,000 pounds of active 15 ingredient (HSDB 2005). The U.S. EPA has tolerances set for crops on which fenamiphos is 16 used and for food commodities imported into the U.S. (U.S. EPA 2002). 17 TABLE 2. Chemical and Physical Properties Parameter Value References Nemacur; Nemacur PR; Phenamiphos; Phosphoramidic acid; ENT 27572; Bay HSDB 2005 Synonyms 68138, Bayer 68138, SRA-3886, Ethyl NIOSH 2005 3-methyl-4-(methylthio)phenyl(1- ACGIH 2006 methylethyl)-phosphoramidate Chemical formula C13H22NO3PS HSDB 2005 Molecular weight 303.36 HSDB 2005 CAS Reg. No. 22224-92-6 HSDB 2005 Technical fenamiphos- off-white to tan, ACGIH 2006 waxy solid. Physical state Colorless crystals; IPCS CEC 2005 Pure fenamiphos: white crystals IPCS 1994 329 mg/L at 20ºC HSBD 2005 Solubility in water 329 mg/L (crystals) O’Neil 2001 700 mg/L at 20°C IPCS 1994 4.7 x 10-5 torr at 20°C ACGIH 2006 Vapor pressure 1 x 10-7 mm HG at 25°C HSDB 2005 Vapor density (air =1) 1.191 at 23ºC HSDB 2005 Liquid density (water =1) - - ° ° ACGIH 2006 Melting point 49.2 C (pure); 40 C (technical)

Boiling point 450°C U.S. EPA 1987 Flammability limits - - 1.0 ppm = 12.4 mg/m3 ACGIH 2006 Conversion factors 3 1.0 mg/m = 0.08 ppm 18 19 20 2. HUMAN TOXICITY DATA 21 2.1. Acute Lethality 22 23 No data were located. 24

9 FENAMIPHOS PROPOSED: November 2009

1 2.2. Nonlethal Toxicity 2 2.2.1. Odor Threshold/Odor Awareness 3 4 No data were located. 5 6 2.2.2. Case Reports 7 8 Incidence reports of poisoning from fenamiphos noted nausea, vomiting, and abdominal 9 pain as effects of exposure (U.S. EPA 2002). The routes of exposure, concentrations, and 10 durations were not specified. 11 12 2.2.3. Exposure Studies 13 14 Knaak et al. (1986) measured inhalation exposure to fenamiphos in workers at a pesticide 15 application firm. Two mixer/loader workers were monitored for 2 hours during the workday. 16 Two applicator workers were monitored for 2.5 hours during the workday. Two additional 17 workers (mixer/loaders and applicators) were monitored for 4 hours during the workday. 18 Personal air pumps attached to shirt collars were used to measure fenamiphos concentration. 19 The sampling device consisted of a sampling tube connected in series with a fiberglass 20 particulate filter. The samples were analyzed by gas chromatography. Inhalation values were at 21 or below the detectable level of 0.001 mg/hour in all workers. 22 23 2.3. Neurotoxicity 24 25 No data were located. 26 27 2.4. Developmental/Reproductive Toxicity 28 29 No data were located. 30 31 2.5. Genotoxicity 32 33 No data were located. 34 35 2.6. Carcinogenicity 36 37 Fenamiphos is not classifiable as a human carcinogen (ACGIH 2006). There were no 38 data to evaluate inhalation carcinogenicity under EPA’s IRIS program (U.S. EPA 1990). 39 40 2.7. Summary 41 42 Very few inhalation data are available for humans. In the data that were located, 43 fenamiphos toxicity was similar to that of other cholinesterase inhibitors in terms of effects. The 44 monitoring study revealed that very little fenamiphos is inhaled during mixing, loading, and 45 application. 46 47 3. ANIMAL TOXICITY DATA 48 3.1. Acute Lethality 49 10 FENAMIPHOS PROPOSED: November 2009

1 3.1.1. Rats 2 3 Kimmerle (1972) exposed male and female Wistar II rats (20/sex/group) to fenamiphos 4 for 1 hour and observed the animals for 14 days. The exposure was carried out in a dynamic 5 inhalation apparatus in which fenamiphos was mixed with polyethylene glycol and ethanol (1:1) 6 and aerosolized. The concentration of fenamiphos in the chamber was determined by 7 spectrophotometry. The male rats were exposed to 0.029, 0.075, 0.087, 0.103, 0.140, 0.165, or 8 0.187 mg/L (29, 75, 87, 103, 140, 165, or 187 mg/m3). The female rats were exposed to 0.029, 9 0.070, 0.105, 0.117, 0.148, 0.170, 0.185, 0.195, or 0.320 mg/L (29, 70, 105, 117, 148, 170, 185, 10 195, or 320 mg/m3). All rats in all the groups except those exposed to 0.029 mg/L (29 mg/m3) 11 had inhibition of cholinesterase activity within 10-60 minutes of exposure. Mortality occurred at 12 concentrations greater than 0.029 mg/L (29 mg/m3) in both sexes as shown in Table 3. The 3 3 13 calculated LC50 for male rats was 0.11 mg/L (110 mg/m ) and was 0.150 mg/L (150 mg/m ) for 3 3 14 female rats. The calculated BMCL05 was 54.181 mg/m for male rats and 112.538 mg/m for 3 3 15 female rats. The BMC01 was 53.035 mg/m for male rats and 98.4546 mg/m for female rats 16 using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008). 17 18 Thyssen (1979a) exposed male and female TNO/W 74 rats (10/sex/group) to fenamiphos 19 (89.8% pure) for 1 or 4 hours and determined the LC50. The rats were exposed nose-only in a 20 dynamic inhalation apparatus. The chamber concentration was analytically determined by 21 spectrophotometry. In the 1-hour exposure study, male and female rats were exposed to 83, 119, 22 145, 148, or 250 mg/m3. All rats in all the groups exhibited signs of cholinesterase inhibition 23 including muscle twitching and cramps which lasted for up to 7 hours post exposure. Inactivity 24 and stiff gait were observed in the rats for up to 5 days post exposure. Heavy drowsiness and 25 breathing disorders were observed at the highest concentrations. Mortality occurred at all 26 concentrations in male rats except 83 mg/m3 and in female rats at the three highest 27 concentrations as shown in Table 3. The 1-hour LC50s for male and female rats were 131 and 3 3 28 130 mg/m , respectively. The calculated BMCL05 was 86.1218 mg/m for male rats and 113.898 3 3 3 29 mg/m for female rats. The BMC01 was 98.6107 mg/m for male rats and 122.75 mg/m for 30 female rats using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008). 31 32 In the 4-hour exposure study, male and female rats were exposed to 57, 62, 100, or 155 33 mg/m3. An additional group of female rats was exposed to 191 mg/m3. All exposed rats 34 exhibited signs of cholinesterase inhibition similar to those observed in rats exposed for only 1 35 hour. Mortality occurred in both sexes as shown in Table 3. The female rats appeared to be 36 more sensitive than male rats as indicated by mortality at lower concentrations. The 4-hour LC50 3 3 37 was 100 mg/m for both sexes. The calculated BMCL05 was 59.2137 mg/m for male rats and 3 3 38 46.6337 mg/m for female rats. The BMC01 was 81.6062 mg/m for male rats and 49.4464 39 mg/m3 for female rats using the Benchmark Dose Software, version 2.0 (U.S. EPA 2008). 40 41 The 4-hr LC50 for acute inhalation exposure in male and female THO/W74 rats was > 0.1 42 mg/L (100 mg/m3). No other data were reported (U.S. EPA 1999). 43 44

11 FENAMIPHOS PROPOSED: November 2009

TABLE 3. Summary of Acute Inhalation Data for Fenamiphos in Laboratory Animals Concentration Species Exposure Time Effect Reference (mg/m3) 29 No effect 75 5% mortality; (1/20) 87 30% mortality, (6/20) Rat 103 60% mortality; (12/20) 1 hr Kimmerle 1972 male 140 65% mortality; (13/20) 165 95% mortality; (19/20) 187 100% mortality; (20/20) 110 LC50 29 No effect 70 Cholinesterase activity inhibition 105 5% mortality; (1/20) 117 Cholinesterase activity inhibition Rat 148 35% mortality; (7/20) 1 hr Kimmerle 1972 female 170 60% mortality; (12/20) 185 90% mortality; (18/20) 195 90% mortality; (18/20) 320 100% mortality; (20/20) 150 LC50 83 Cholinesterase activity inhibition 119 20% mortality, (2/10) Rat 145 60% mortality, (6/10) 1 hr Thyssen 1979a male 148 90% mortality, (9/10) 250 100% mortality, (10/10) 131 LC50 83 Cholinesterase activity inhibition 119 Cholinesterase activity inhibition Rat 145 70% mortality, (7/10) 1 hr Thyssen 1979a female 148 90% mortality, (9/10) 250 100% mortality, (10/10) 130 LC50 57 Cholinesterase activity inhibition 62 Cholinesterase activity inhibition Rat 100 4 hr 60% mortality, (6/10) Thyssen 1979a male 155 100% mortality, (10/10) 100 LC50 57 Cholinesterase activity inhibition 62 10% mortality, (1/10) Rat 100 50% mortality, (5/10) 4 hr Thyssen 1979a female 155 90% mortality, (9/10) 191 100% mortality, (10/10) 100 LC50 Rat 100 4 hr Less than the LC50 U.S. EPA 1999 1 2 3 3.2. Nonlethal Toxicity 4 3.2.1. Rats 5 Repeat Dose 6 7 Male and female Wistar rats (10/sex/group) were exposed via inhalation to 0, 0.03, 0.25, 8 or 3.5 µg/L fenamiphos (0, 30, 250, or 350 mg/m3) for 6 hours/day, 5 days/week, for 21 days 9 (Thyssen 1979b; U.S. EPA 1999). No overt cholinergic symptoms were observed, and there 10 were no changes in physical appearance, behavioral patterns, body weight, hematology, clinical 11 chemistry, urinalysis, gross pathology, or organ weights. Plasma cholinesterase activity was 12 inhibited in males and females, 42-47% and 72-78%, respectively. Erythrocyte cholinesterase 13 activity was inhibited in female rats 15-19%. Brain cholinesterase activity in the treated rats was 14 comparable to that of control rats. The LOAEL was 350 mg/m3, and the NOAEL was 250 12 FENAMIPHOS PROPOSED: November 2009

1 mg/m3. No details were reported on atmosphere generation and analysis. 2 3 3.3. Developmental/Reproductive Toxicity 4 5 No inhalation developmental/reproductive studies were located. 6 7 Groups of rabbits were given fenamiphos by oral gavage at doses of 0, 0.1, 0.3, or 1.0 8 mg/kg on days 6-18 of pregnancy. A hint of maternal toxicity was shown by a trend toward 9 decreases in body weight gain at the highest two doses. The chemical was not fetotoxic or 10 embryotoxic at any dose; no statistically significant differences were seen in the mean numbers 11 of corpora lutea or implants, in implantation efficiency, litter size or sex ratio, or in the number 12 or percent of live or resorbed fetuses. The authors concluded that the finding of a fused “chain” 13 of sternebrae in five fetuses at the highest dose may have been a treatment-related anomaly, but 14 noted that the anomaly appeared at a maternally-toxic dose (Hazleton Raltech Inc. 1982). 15 16 Chinchilla rabbits (16/group) were given fenamiphos technical by oral gavage at doses of 17 0, 0.1, 0.5, or 2.5 mg/kg on days 6-18 of pregnancy. While no maternal toxicity was seen at the 18 lower two doses, maternal toxicity at the highest dose was shown by numerous cholinergic 19 effects and four treatment-induced deaths, decreased body weight gain, and decreased food 20 consumption. No effects were seen on the mean number of corpora lutea, number of live or dead 21 fetuses, litter size, sex ratio, or number of live or resorbed fetuses. At the highest dose only, 22 there was a slight reduction in mean live pup weight as well as an increase in preimplantation 23 loss. The only visceral anomaly seen was one malformation in the high dose group (Becker 24 1986; U.S. EPA 1999). 25 26 Long Evans rats (25/dose) were given fenamiphos by oral gavage at doses of 0, 0.3, 1.0, 27 or 3.0 mg/kg on days 6-15 of pregnancy. There were no treatment-related effects on the numbers 28 of live fetuses or abnormal fetuses at any dose level, and there was no increase in the incidence 29 of fetuses with gross visceral or skeletal anomalies. At the highest dose, evidence of toxicity to 30 the pregnant dams was seen and cholinergic signs were seen within 30 minutes after treatment. 31 Two dams in that group died, although the cause of death was not determined (Schlueter 1981). 32 33 Sprague-Dawley (Crl:CDBR) rats were given fenamiphos by oral gavage at doses of 0, 34 0.25, 0.85, or 3.0 mg/kg on days 6-15 of pregnancy. Five females per group were killed on day 35 16 of pregnancy, and the rest at day 20 of pregnancy, for examination of uterine contents. At the 36 highest dose, all pregnant dams exhibited tremors, and 6 died during the treatment period. At 37 that dose level, body weight and food consumption were also reduced, and plasma and RBC (but 38 not brain) cholinesterase activity were significantly inhibited at 16 days of pregnancy. At 20 39 days of pregnancy (5 days after the treatment regimen ended), there was no significant inhibition 40 of plasma cholinesterase activity, and there was less inhibition of RBC cholinesterase activity 41 than was seen one day after the treatment regimen ended. No treatment-related maternal effects 42 were seen at the lower doses, and no embryotoxicity or teratogenicity was observed at any dose 43 level. There was no effect on fetal brain cholinesterase activity; brain cholinesterase activity was 44 the only cholinesterase tested in fetuses (Astroff and Young 1998). 45 46 In a 3-generation reproduction study, fenamiphos was fed to rats at concentrations of 0, 3, 47 10 or 30 ppm (equivalent to about 0, 0.15, 1.0, or 1.5 mg/kg/day as estimated by the EPA). At 48 the highest dose there was a reduction of body weight gain in the F2b generation males only. 49 There were no significant effects on fertility, litter size or pup weight, and no malformed pups 13 FENAMIPHOS PROPOSED: November 2009

1 were seen at any treatment level. Histopathological examination revealed no treatment-related 2 effects in the F3b generation (Löser 1972). 3 4 In a 2-generation reproduction study, fenamiphos was fed to Sprague-Dawley rats at 5 concentrations of 0, 2.5, 10 or 40 ppm (0, 0.2, 0.73, or 3.2 mg/kg/day in females or 0, 0.17, 0.64, 6 or 2.8 mg/kg/day in males). There were no treatment-related endocrine or reproductive effects or 7 clinical signs seen in either adults or pups. However, at the highest dose, F1 pups showed 8 decreased body weight gain during lactation, and F0 and F1 females had reduced body weight 9 during lactation. Also at the highest dose, body weight of adult rats was significantly reduced at 10 the end of the experiment, and absolute and relative ovary weights were significantly decreased. 11 Plasma cholinesterase activity was significantly inhibited at all concentrations in adult females 12 but only at 10 and 40 ppm in adult males. RBC cholinesterase activity was significantly inhibited 13 at 10 ppm (but not at 40 ppm) in adults of both sexes as well as in 4-day-old pups. Brain 14 cholinesterase activity was significantly inhibited at 40 ppm in adults of both sexes but not in 15 pups, in which this activity was measured at 4 and 21 days of age (Eigenberg 1991). 16 17 3.4. Genotoxicity 18 19 Fenamiphos was not mutagenic in the dominant lethal test with NMRI mice (Herbold and 20 Lorke 1980). 21 22 Fenamiphos did not cause an increase in sister chromatid exchange in Chinese hamster 23 V-79 cells without S9 activation (Chen et al. 1982a) or with S9 activation (Chen et al. 1982b). 24 25 Fenamiphos was negative in the Ames test both with and without metabolic activation 26 using the following Salmonella typhimurium strains: TA1535, TA1537, TA1538, TA98, and 27 TA100 (Herbold 1985). 28 29 Results are considered equivocal in chromosomal aberration induction because 30 aberrations were induced only in the cytotoxic range (based on a significant reduction in the 31 mitotic index) in human lymphocytes with and without metabolic activation. Hemolysis also 32 occurred in the cells that yielded the positive result with metabolic activation (Herbold 1987). 33 34 3.5. Chronic Toxicity/Carcinogenicity 35 36 No inhalation data were located. 37 38 3.6. Summary 39 40 Fenamiphos exposure caused decreased plasma and erythrocyte cholinesterase activity 41 similar to other organophosphate pesticides. Information on the lethality of fenamiphos 42 following inhalation exposure was limited to rats. Signs of cholinesterase activity inhibition 43 were observed in male and female rats. Fenamiphos has a steep exposure-response curve. Male 44 rats experienced 5% mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 45 mg/m3; and 60% mortality at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 46 (Kimmerle 1972). In a study by Thyssen (1979a), 20% of the male rats died after exposure to 47 119 mg/m3 for 1 hour; 60% died after exposure to 145 mg/m3; and 90% died after exposure to 48 148 mg/m3. Female rats had 70% mortality at 145 mg/m3 and 90% mortality after exposure to 49 148 mg/m3 for 1 hour. In a 4-hour study by Thyssen (1979a), male rats experienced 60% 14 FENAMIPHOS PROPOSED: November 2009

1 mortality at 100 mg/m3 and 100% mortality at 155 mg/m3, and female rats experienced 50% 2 mortality at 100 mg/m3; 90% mortality at 155 mg/m3; and 100% mortality at 191 mg/m3. The 1- 3 3 3 hour LC50 ranged from 100 to 155 mg/m , and the 4-hour LC50 values were 100 mg/m or 4 greater. 5 6 4. SPECIAL CONSIDERATIONS 7 4.1. Metabolism and Disposition 8 9 Fenamiphos is absorbed from the gastrointestinal tract, by inhalation, or through intact 10 skin. It is oxidized to form sulfoxide and sulfone analogs (HSDB 2005). In an in vitro study 11 using rat liver preparations, fenamiphos was metabolized to its sulfoxide, an N-alkylated 12 product, and an unidentified product (ACGIH 2006). No information was located regarding 13 absorption in humans or animals after inhalation exposure to fenamiphos. Oral studies have 14 shown that distribution following oral absorption is rapid and excretion occurs within 8 hours of 15 the administered dose. A single oral exposure to 6 mg/kg fenamiphos in rats yielded a half-life 16 in brain of 100 hours and a half-life in plasma of 212 hours (HSDB 2005; ACGIH 2006). 17 Fenamiphos given to rats at 0.3 or 3 mg/kg both orally and by i.p. injection, was completely and 18 rapidly absorbed and eliminated, with 99% of the dose gone by 48 hours after treatment. 19 Residues found in the bodies represented only 0.045-0.23% of the amount of fenamiphos 20 administered. The great majority (96-98%) was eliminated in the urine, with the rest being 21 eliminated in feces. Treatment with fenamiphos for 14 days prior to treatment with 22 [14C]fenamiphos did not change the absorption, distribution, or elimination patterns (ACGIH 23 2006). The proposed metabolic pathway of fenamiphos is shown in Figure 1 (IPCS 1997). 24

15 FENAMIPHOS PROPOSED: November 2009

1 2 3 4.2. Mechanism of Toxicity 4 5 Fenamiphos directly inhibits cholinesterases. The sulfoxide and sulfone metabolites of 6 fenamiphos are more potent inhibitors than fenamiphos itself (ACGIH 2006). Inhibition of 7 cholinesterase results in the accumulation of acetylcholine in the synaptic cleft which continues 8 to stimulate the nicotinic and muscarinic receptors leading to increased secretions, 9 bronchoconstriction, gastrointestinal cramps, muscle fasciculation, tremors, weakness, mental 10 confusion, miosis, coma, and death. There is evidence that overstimulation of the receptors by 11 acetylcholine causes desensitization and down-regulation of receptor numbers that causes 12 persistent muscle weakness (Ecobichon 2001). 13 14 4.3. Structure Activity Relationships 15 16 Although all organophosphate cholinesterase inhibitors have the same mechanism of

16 FENAMIPHOS PROPOSED: November 2009

1 action, their potency and physicochemical properties vary. The physicochemical differences 2 affect environmental persistence and metabolic fate. Development of AEGL values by structure- 3 activity analysis would be tenuous and uncertain without rigorous relative potency data. 4 5 4.4. Other Relevant Information 6 4.4.1. Species Variability 7 8 Variability in types of esterases and their respective activity is important in determining 9 interspecies variability in organophosphate poisoning. This affects susceptibility to 10 organophosphates due to differences in detoxification potential (NRC 2003). Baseline red blood 11 cell acetylcholinesterase activity is slightly higher in humans (12.6 μmol/mL/min) than in 12 monkeys (7.1 μmol/mL/min) and much higher compared to other species (4.7 μmol/mL/min for 13 pigs; 4.0 μmol/mL/min for goats; 2.9 μmol/mL/min for sheep; 2.4 μmol/mL/min for mice; 2.0 14 μmol/mL/min for dogs; 2.7 μmol/mL/min for guinea pigs; 1.7 μmol/mL/min for both rats and 15 rabbits; and 1.5 μmol/mL/min for cats) (Ellin 1981). Similarly, humans tend to have greater 16 plasma cholinesterase activity levels than other species (Wills 1972). In humans, approximately 17 50% of the total blood cholinesterase consists of plasma cholinesterase. Plasma cholinesterase 18 activity constitutes approximately 40% of the total blood cholinesterase in dogs, 30% in rats, 19 20% in monkeys, and only 10% in sheep, horses, and cows. Both of these findings suggest that 20 humans will have greater potential for buffering the activity of organophosphate 21 anticholinesterases by preventing interaction with red blood cell and brain cholinesterase as well 22 as cholinesterase at neuromuscular junctions (NRC 2003). Carboxylesterases known to occur in 23 human erythrocytes, liver, lung, skin, and nasal tissue may also contribute to detoxification of 24 organophosphates but the quantitative aspect of this has not been fully characterized (NRC 25 2003). 26 27 4.4.2. Susceptible Populations 28 29 Individual variability in plasma cholinesterase activity is well documented (NRC 2003). 30 This variability includes age-related differences (neonates are more susceptible than adults), 31 gender differences (females tend to have approximately 10% lower plasma and red blood cell 32 cholinesterase activity), and genetic variations in plasma cholinesterase activity. This genetically 33 determined variability, sometimes resulting in greatly reduced (64% of normal) activity of 34 plasma cholinesterase may impart deficiencies in ability to detoxify organophosphates such as 35 fenamiphos. Additionally, polymorphic variability in A-esterases such as paraoxonase/ 36 arylesterase, may contribute to individual variability in organophosphate ester detoxification 37 processes (NRC 2003). 38 39 4.4.3. Concentration-Exposure Duration Relationship 40 41 The concentration-time relationship for a single endpoint for many irritant and 42 systemically acting vapors and gases may be described by Cn x t = k (ten Berge et al. 1986). 43 Exposure-response data for time-scaling were available for two time points, 1 and 4 hours. The 44 estimation ratio between regression coefficients of ln (concentration) and ln (minutes) was 4.8 45 (Appendix B). 46 47 4.4.4. Concurrent Exposure Issues 48 49 Both concurrent exposure to other organophosphates and simultaneous exposure via other 17 FENAMIPHOS PROPOSED: November 2009

1 exposure routes are of concern. Fenamiphos may enter the body and be bioavailable by 2 dermal, oral, and inhalation pathways. Animal studies show that fenamiphos is readily absorbed 3 through the skin and gastrointestinal tract, as evidenced by its high acute toxicity via these routes 4 of exposure (ACGIH 2006). 5 6 5. DATA ANALYSIS FOR AEGL-1 7 5.1. Summary of Human Data Relevant to AEGL-1 8 9 No human data relevant to derivation of AEGL-1 values were available. 10 11 5.2. Summary of Animal Data Relevant to AEGL-1 12 13 Kimmerle (1972) exposed male and female Wistar II rats to 29 mg/m3 fenamiphos for 1 14 hour. The rats did not exhibit any signs of cholinesterase activity inhibition, and no mortality 15 occurred in these rats. 16 17 5.3. Derivation of AEGL-1 18 19 No AEGL-1 values were established because the AEGL-1 values were too close to, or 20 exceeded AEGL-2 values. If a point of departure of 29 mg/m3 (no effect level) was used to 21 derive AEGL-1 values, values of 1.4, 1.1, 0.97, 0.72, and 0.63 mg/m3 for the 10-minute, 30- 22 minute, 1-hour, 4-hour, and 8-hour time points, respectively, would exceed the AEGL-2 values 23 (Appendix A). 24 TABLE 4. AEGL-1 Values for Fenamiphos 10-minute 30-minute 1-hour 4-hour 8-hour NR NR NR NR NR 25 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 26 27 6. DATA ANALYSIS FOR AEGL-2 28 6.1. Summary of Human Data Relevant to AEGL-2 29 30 No human data relevant to derivation of AEGL-2 values were available. 31 32 6.2. Summary of Animal Data Relevant to AEGL-2 33 34 No animal data relevant to derivation of AEGL-2 were located. 35 36 6.3. Derivation of AEGL-2 37 38 The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of 39 experimental data and the steep exposure-response relationship justify estimating AEGL-2 40 values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5% 41 mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 mg/m3; and 60% mortality 42 at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by 43 Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died 44 after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70% 45 mortality at 145 mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour 46 study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100% 18 FENAMIPHOS PROPOSED: November 2009

1 mortality at 155 mg/m3, and female rats experienced 50% mortality at 100 mg/m3; 90% mortality 2 at 155 mg/m3; and 100% mortality at 191 mg/m3. The resulting AEGL-2 values compared to the 3 values derived from the no effect level demonstrate the conservative nature of using the 3-fold 4 reduction approach to derive AEGL-2 values. AEGL-2 values are shown in Table 5. 5 TABLE 5. AEGL-2 Values for Fenamiphos 10-minute 30-minute 1-hour 4-hour 8-hour 1.0 mg/m3 0.80 mg/m3 0.70 mg/m3 0.53 mg/m3 0.43 mg/m3 6 7 7. DATA ANALYSIS FOR AEGL-3 8 7.1. Summary of Human Data Relevant to AEGL-3 9 10 No human data relevant to derivation of AEGL-3 values were available. 11 12 7.2. Summary of Animal Data Relevant to AEGL-3 13 3 3 14 Kimmerle (1972) calculated a 1-hour LC50 of 100 mg/m for male rats and 150 mg/m for 3 15 female rats. Using the exposure-response data from this study, a BMCL05 of 54.181 mg/m 3 3 3 16 (male) and 112.538 mg/m (female) and BMC01 of 53.035 mg/m (male) and 98.4546 mg/m 17 (female) were calculated using Benchmark Dose Software, version 2.0 (U.S. EPA 2008). 3 3 18 Thyssen (1979a) calculated a 1-hour LC50 of 131 mg/m for male rats and 131 mg/m for female 3 3 19 rats. The calculated BMCL05 was 86.1218 mg/m for male rats and 113.898 mg/m for female 3 3 20 rats. The BMC01 was calculated to be 98.6107 mg/m for male rats and 122.75 mg/m for female 3 21 rats. The 4-hour LC50 was 100 mg/m for both sexes. The calculated BMCL05 was 59.2137 3 3 3 22 mg/m for male rats and 46.6337 mg/m for female rats. The BMC01 was 81.6062 mg/m for 23 male rats and 49.4464 mg/m3 for female rats (see Appendix E). 24 25 7.3. Derivation of AEGL-3 26 27 Due to the availability of group-specific response data, the Thyssen (1979a) report was 3 28 selected as the key study, and the female rat 4-hour BMCL05 of 46.6337 mg/m was selected as 29 the point of departure for AEGL-3 derivation. This is considered a threshold for lethality and is 30 the most conservative benchmark value calculated from the test animal used in the study. 31 Lethality data were sufficient for empirical derivation of a time-scaling factor (n) for use in the 32 equation Cn x t = k. The value of n was 4.8 and was used to time scale AEGL values. As 33 described in Sections 4.2 and 4.4, the mechanism of action of organophosphate anti- 34 cholinesterases is well understood; their activity on cholinergic systems has been shown to be the 35 same across species. Variability in responses is primarily a function of varying cholinesterase 36 levels and types of cholinesterase. Humans have greater levels of plasma cholinesterase than do 37 other species which allows for greater binding of anticholinesterase compounds such as 38 fenamiphos, thereby decreasing the availability of the compound to critical targets such as brain 39 cholinesterase. Therefore, the interspecies uncertainty factor is limited to 3. The documented 40 variability in sensitivity among different age groups and genders, and the known genetic 41 polymorphisms in A-esterases justify retention of the intraspecies uncertainty factor of 10. The 42 uncertainty factor application and rationale are the same as those applied in the derivation of 43 other organophosphate anticholinesterases (NRC 2003). The AEGL-3 values for fenamiphos are 44 shown in Table 6, and the derivation is presented in Appendix A. 45

19 FENAMIPHOS PROPOSED: November 2009

TABLE 6. AEGL-3 Values for Fenamiphos 10-minute 30-minute 1-hour 4-hour 8-hour 3.0 mg/m3 2.4 mg/m3 2.1 mg/m3 1.6 mg/m3 1.3 mg/m3 1 2 8. SUMMARY OF AEGLS 3 8.1. AEGL Values and Toxicity Endpoints 4 5 Very limited data are available regarding the inhalation toxicity of fenamiphos. Data 6 were available with which to derive AEGL-1 values, however, those values would have 7 exceeded AEGL-2 values. Therefore, AEGL-1 values are not recommended. Exposure- 8 response data for AEGL-2 tier severity effects were not available for single acute exposures. 9 However, the exposure-response curve for fenamiphos, like most organophosphate 10 anticholinesterases is steep, thereby allowing for estimation of the AEGL-2 values by a three- 11 fold reduction of the AEGL-3 values (NRC 2001; 2003). The AEGL-3 values were based upon 3 12 the estimated lethality threshold (BMCL05 of 46.6337 mg/m ) in female rats exposed for 4 hours. 13 AEGL values are summarized in Table 7. 14 TABLE 7. Summary of AEGL Values Exposure Duration Classification 10-minute 30-minute 1-hour 4-hour 8-hour AEGL-1 NR NR NR NR NR (Nondisabling) AEGL-2 1.0 mg/m3 0.80 mg/m3 0.70 mg/m3 0.53 mg/m3 0.43 mg/m3 (Disabling) AEGL-3 3.0 mg/m3 2.4 mg/m3 2.1 mg/m3 1.6 mg/m3 1.3 mg/m3 (Lethal) 15 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 16 17 8.2. Comparison with Other Standards and Guidelines 18 19 AEGL values for fenamiphos are compared to other guidelines and standards for this 20 compound (Table 8). The AEGL values for fenamiphos are slightly lower than the other 21 guidelines and standards. The majority of the guidelines and standards were based on repeated 22 dose inhalation, oral toxicity, and dermal toxicity data in animals rather than acute inhalation 23 data. 24 25

20 FENAMIPHOS PROPOSED: November 2009

TABLE 8. Extant Standards and Guidelines for Fenamiphos Exposure Duration Guideline 10 minute 30 minute 1 hour 4 hour 8 hour AEGL-1 NR NR NR NR NR AEGL-2 1.0 mg/m3 0.80 mg/m3 0.70 mg/m3 0.53 mg/m3 0.43 mg/m3 AEGL-3 3.0 mg/m3 2.4 mg/m3 2.1 mg/m3 1.6 mg/m3 1.3 mg/m3 REL-TWA 0.1 mg/m3

(NIOSH)a (skin) TLV-TWA 0.05 mg/m3

(ACGIH)b (IFV, skin) MAC-Peak 0.1 mg/m3 Category (The Netherlands)c 1 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 2 IFV= inhalable fraction and vapor 3 4 a NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - Time Weighted 5 Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA. 6 7 b ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time Weighted 8 Average) (ACGIH 2008) is the time-weighted average concentration for a normal 8-hour workday and a 40-hour work 9 week, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect 10 11 c MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers 12 [under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined 13 analogous to the ACGIH-Ceiling. 14 15 8.3. Data Adequacy and Research 16 17 Although toxicity data for fenamiphos are available for oral and dermal exposure routes, 18 acute inhalation data are limited. Limited quantitative data are available regarding human 19 inhalation exposures and very few detailed data regarding health effects from fenamiphos 20 exposure are documented. Animal inhalation studies were found for only one species and most 21 of the studies lacked data on effects other than death. The most useful data to allow for a more 22 robust analysis relative to AEGL development would be dose-response data identifying AEGL-2 23 severity effects. 24

21 FENAMIPHOS PROPOSED: November 2009

1 2 9. REFERENCES 3 4 ACGIH (American Conference of Governmental Industrial Hygienists). 2008. Threshold limit 5 values (TLVs) for chemical and physical agents and biological exposure indices (BEIs). ACGIH, 6 Cincinnati, OH. 7 8 ACGIH (American Conference of Governmental Industrial Hygienists). 2006. Fenamiphos. 9 Documentation of the Threshold Limit Values. 2006 Supplement to the 7th Edition. 1330 Kemper 10 Meadow Drive, Cincinnati, OH. 11 12 AIHA (American Industrial Hygiene Association). 2008. Emergency Response Planning Guide 13 Guideline (ERPG). Fairfax, VA: AIHA 14 15 Astroff, A.B., Young, A.D. 1998. The relationship between maternal and fetal effects following 16 maternal organophosphate exposure during gestation in the rat. Toxicol. Industrial Health 14:869- 17 889. 18 19 Becker, H. 1986. Embryotoxicity (including teratogenicity) study with SRA 3886 (nemacur) in the 20 rabbit. Report no. 94392. Unpublished study prepared by Research and Consulting Company AG for 21 Bayer, Stilwell, KS; submitted to U.S. EPA, MRID 40347602. U.S. EPA, FOI, Washington, DC. 22 (Cited in ACGIH 2006). 23 24 Chen, H.H., Sirianni, S.R., Huang, C.C. 1982a. Sister chromatid exchanges and cell-cycle delay in 25 Chinese hamster V79 cells treated with nine organophosphorus compounds (8 pesticides and 1 26 defoliant). Mutat. Res. 103:307-313. 27 28 Chen, H.H., Sirianni, S.R., Huang, C.C. 1982b. Sister chromatid exchanges in Chinese hamster ovary 29 cells treated with seventeen organophosphorus compounds in the presence of a metabolic activation 30 system. Environ. Mutagen. 4:621-624. 31 32 DFG (Deutsche Forschungsgemeinschaft). 2007. List of MAK and BAT Values 2007. 33 Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, 34 Report No. 43. Weiheim, Federal Republic of Germany: Wiley VCH. 35 36 Ecobichon, D.J. 2001. Toxic Effects of Pesticides. Casarett & Doull’s Toxicology: The Basic 37 Science of Poisons, 6th Ed., C.D. Klaassen, ed. New York: McGraw-Hill. pp. 774-784. 38 39 Eigenberg, D.A. 1991. A two-generation dietary reproduction study in rats using fenamiphos (Nemacur). 40 Unpublished report. Bayer, Stilwell, KS; submitted to U.S. EPA, MRID 42491701 supplement to 41 MRID 41908901. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 42 43 Ellin, R. I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorous 44 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 45 Biomedical Laboratory, Report No. USABML-SP-81-003. Aberdeen Proving Ground, MD. DTIC, 46 AD A1010364. 47 48 Haber, F.R. 1924. Zur geschichte des gaskrieges [On the history of the gas war]. In: Fuenf Vortraege aus 49 den Jahren 1920-23 [Five lectures from the years 1920-1923]. Berlin, Germany: Verlag von Julius 50 Springer; pp. 76-92. 51 52 Hazleton Raltech, Inc. 1982. Teratology study with Nemacur in rabbits. Unpublished final report. 53 Bayer, Stilwell, KS; submitted to US. EPA, MRID 00121286. U.S. EPA, FOI, Washington, DC. 22 FENAMIPHOS PROPOSED: November 2009

1 (Cited in ACGIH 2006). 2 3 Herbold, B. 1987. SRA 3886: Cytogenetic study of human lymphocyte cultures in vitro to test 4 for chromosome damage: Lab project ID 94393. Unpublished study prepared by Bayer AG; 5 submitted to US EPA, MRID 40163501. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 6 7 Herbold, B. 1985. Fenamiphos: Salmonella/microsome test to evaluate for potential point 8 mutation: Report no. 89087, supplemental submission. Unpublished study prepared by Bayer AG; 9 submitted to U.S. EPA, MRID 40319001. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 10 11 Herbold, B., Lorke, D. 1980. SRA 3886: Dominant lethal study on male mouse to test for mutagenic 12 effects: Report n.8838 69377. Unpublished study received 11/09/1981 under 3125-237; prepared by 13 Bayer AG, West Germany, submitted by Mobay Chemical Corp., Kansas City, MO [CDL:246210- 14 A]; submitted to U.S. EPA, MRID 00086981. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 15 2006). 16 17 HSDB (Hazardous Substances Data Bank). 2005. Fenamiphos. [Online] Available. 18 http://toxnet.nlm.nih.gov/ [07/17/2008]. TOXNET, Toxicology Data Network. US. Natl. Library of 19 Medicine. 20 21 IPCS (International Programme on Chemical Safety). 1997. No 929. Fenamiphos. Pesticide 22 residues in food: 1987 evaluations Part II Toxicology & Environmental. [Online] Available. 23 http://www.inchem.org/documents/jmpr/jmpmono/v097pr06.htm. [09/05/2008]. 24 25 IPCS (International Programme on Chemical Safety). 1994. WHO (World Health 26 Organization)/FAO (Food and Agriculture Organization of the United Nations) Data Sheet on 27 Pesticides No. 92. [Online] Available. http://www.inchem.org/documents/pds/pds/pest92_e.htm. 28 [08/28/2008]. 29 30 IPCS, CEC (International Programme on Chemical Safety, Commission of the European 31 Communities). 2005. International Chemical Safety Card. [Online] Available. 32 http://www.inchem.org/documents/icsc/icsc/eics0483.htm. [08/28/2008]. 33 34 Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active ingredient on rats. 35 Unpublished report. Bayer AG, Wuppertal, Germany. 36 37 Knaak, J.B., Jacobs, K.C., Wang, G.M. 1986. Estimating the hazard to humans applying 38 Nemacur 3EC with rat dermal-dose ChE response data. Bull. Environ. Contam. Toxicol. 37:159- 39 163. 40 41 Löser, E. 1972. BAY 68 138 generation studies on rats. Reports no. 3424 and 34029. 42 Unpublished study; received 05/23/1973 under 3F1399. Prepared by Farbenfabriken Bayer, AG, 43 submitted by Chemargo Corp., Kansas City; MO [CDL:093742-M]; submitted to EPA, MRID 44 00037979. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 45 46 NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to 47 Chemical Hazards. NIOSH, Cincinnati, OH. [Online] Available. 48 http://www.cdc.gov/niosh/ [04/14/2008]. 49 50 NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately 51 Dangerous to Life and Health Concentrations (IDLH). [Online] Available. 52 http://www.cdc.gov/niosh/idlh/ [09/10/2006]. 53 23 FENAMIPHOS PROPOSED: November 2009

1 NRC (National Research Council). 2003. Acute Exposure Guideline Levels for Selected 2 Airborne Contaminants: Nerve agents GA, GB, GD, GF, and VX. Vol. 3. Committee on 3 Toxicology, Board on Toxicology and Environmental Health Hazards, Commission on Life Sciences, 4 National Research Council. National Academy Press, Washington, DC. 5 6 NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute 7 Exposure Guideline Levels for Hazardous Chemicals. The National Academy Press, Washington, 8 DC. 9 10 NRC (National Research Council). 1985. Emergency and Continuous Exposure Guidance Levels 11 for Selected Airborne Contaminants, Vol. 5. Washington, D.C., National Academy Press. 12 13 O’Neil, M.J., Smith, A., Heckelman, P.E. eds. 2001. The Merck Index, 13th ED. Whitehouse Station, NJ: 14 Merck and Co. 3984. 15 16 OSHA (Occupational Safety and Health Administration). 2005. Code of Federal 17 Regulations, CFR 29, Part 1910, Table Z-1. 18 19 Rinehart, W. E., Hatch, T. 1964. Concentration-time product (CT) as an expression of dose in 20 sublethal exposures to phosgene. Ind. Hyg. J. 25: 545-553. 21 22 SDU Uitgevers 2000. MAC Ministry of Social Affairs and Employment. Nationale 23 MAC (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands. 24 25 Schlueter, G. 1981. SRA 3886 (Nemacur) study of embryotoxic and teratogenic effects on rats 26 after oral administration. Unpublished report; Bayer AG, Wuppertal, Germany; submitted to U.S. 27 EPA, MRID 40347601. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 28 29 ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response 30 relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 301-309. 31 32 Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no. 33 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany. 34 35 Thyssen, J. 1979b. Nemacur active ingredient (SRA 3886) subacute inhalational toxicity study on rats. 36 Report no. 8669. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany; 37 submitted to U.S. EPA, MRID 00154747. U.S. EPA, FOI, Washington, DC. (Cited in ACGIH 2006). 38 39 U.S. EPA (U.S. Environmental Protection Agency). 2008. Benchmark Dose Software. Version 40 2.0 National Center for Environmental Assessment, Office of Research and Development. [Online] 41 Available. http://www.epa.gov/ncea/bmds.htm [04/22/2008]. 42 43 U.S. EPA (U.S. Environmental Protection Agency). 2002. Interim Reregistration Eligibility Decision 44 (IRED) Fenamiphos. EPA 738-R-02-004. U.S. EPA, PPTS (7505C), Washington, DC (May 2002). 45 46 U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticides Programs science policy 47 on the use of data on cholinesterase inhibition for risk assessment of organophosphorus and 48 carbamate pesticides. Office of Pesticides Programs, U.S. EPA, Washington DC. August 18, 2000.

49 U.S. EPA (U.S. Environmental Protection Agency). 1999. Human health risk assessment fenamiphos; J. 50 Cruz, risk assessor, 9/2/1999. Part of EPA special docket EPA-HQ-OPP-2007-0151. 51 52 U.S. EPA (U.S. Environmental Protection Agency). 1990. Integrated Risk Information System. 24 FENAMIPHOS PROPOSED: November 2009

1 [Online] Available. http://www.epa.gov/iris/subst/0240.htm [09/04/2008]. 2 3 U.S. EPA (U.S. Environmental Protection Agency) Federal Emergency Management Agency, U.S. 4 Department of Transportation. 1987. Technical Guidance for Hazards Analysis. EPA-OSWER-88- 5 0001. 6 7 Wills, J.H. 1972. The measurement and significance of changes in the cholinesterase activities of 8 erythrocytes and plasma in man and animals. CRC Crit. Rev. Toxicol. 1:153-202. 9 10 11

25 FENAMIPHOS PROPOSED: November 2009

1 2 3 APPENDIX A: Derivation of AEGL Values 4 5 Derivation of AEGL-1 6 No AEGL-1 values were established because the AEGL-1 values would have been too close to 7 or exceeded AEGL-2 values. 8 9 The calculations for deriving AEGL values from the no effect level are presented below for comparison 10 with AEGL-2 values. 11 12 Key Study: Kimmerle, G. 1972. Acute inhalation toxicity study with Nemacur active 13 ingredient on rats. Unpublished report. Bayer AG, Wuppertal, Germany. 14 15 Toxicity endpoint: Male and female rats exposed to 29 mg/m3 for 1 hour did not exhibit any 16 effects of toxicity. 17 18 Time scaling: Cn x t = k, where n = 4.8 19 20 Uncertainty factors: Total uncertainty factor adjustment is 30. 21 Interspecies: 3: Variability is primarily a function of varying cholinesterase 22 activity levels and types of cholinesterase present; humans have greater 23 levels of plasma cholinesterase with which to bind anticholinesterases such 24 as fenamiphos than do other species. This decreases the dose to critical 25 targets. Therefore, the interspecies uncertainty factor is limited to 3. 26 Intraspecies: 10: The documented variability in sensitivity among different 27 age groups and genders, and the known genetic polymorphisms in A- 28 esterases justify retention of the intraspecies uncertainty factor of 10. 29 30 Modifying factor: None 31 32 Calculation: 29 mg/m3/ 30 = 0.96667 mg/m3 33 C4.8 x t = k 34 (0.96667 mg/m3)4.8 x 60 min = 50.998 mg/m3(4.8)·min 35 36 10-minute AEGL-1 C4.8 x 10 min = 50.998 mg/m3(4.8)·min 37 C= 1.4 mg/m3 38 39 30-minute AEGL-1 C4.8 x 30 min = 50.998 mg/m3(4.8)·min 40 C= 1.1 mg/m3 41 42 1-hour AEGL-1 C4.8 x 60 min = 50.998 mg/m3(4.8)·min 43 C = 0.97 mg/m3 44 45 4-hour AEGL-1 C4.8 x 240 min = 50.998 mg/m3(4.8)·min 46 C = 0.72 mg/m3 47 48 8-hour AEGL-1 C4.8 x 480 min = 50.998 mg/m3(4.8)·min 49 C = 0.63 mg/m3 50

26 FENAMIPHOS PROPOSED: November 2009

1 Derivation of AEGL-2 2 3 4 The AEGL-2 values were derived by dividing the AEGL-3 values by three. The lack of 5 experimental data and the steep exposure-response relationship justify estimating AEGL-2 6 values by a 3-fold reduction of AEGL-3 values (NRC 2001). Male rats experienced 5% 7 mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 mg/m3; and 60% mortality 8 at103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by 9 Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died 10 after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70% 11 mortality at 145 mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour 12 study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100% 13 mortality at 155 mg/m3, and female rats experienced 50% mortality at 100 mg/m3; 90% mortality 14 at 155 mg/m3; and 100% mortality at 191 mg/m3. 15 16 Calculations: 17 18 10-minute AEGL-2 3.0 mg/m3/3 = 1.0 mg/m3 19 20 30-minute AEGL-2 2.4 mg/m3/3 = 0.80 mg/m3 21 22 1-hour AEGL-2 2.1 mg/m3/3 = 0.70 mg/m3 23 24 4-hour AEGL-2 1.6 mg/m3/3 = 0.53 mg/m3 25 26 8-hour AEGL-2 1.3 mg/m3/3 = 0.43 mg/m3 27

27 FENAMIPHOS PROPOSED: November 2009

1 2 3 Derivation of AEGL-3 4 5 Key Studies: Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute 6 inhalational toxicity studies. Report no. 8210. Unpublished study 7 prepared by Bayer AG, Institut fuer Toxikologie, Germany. 8 3 9 Toxicity endpoint: 4-hr BMCL05 of 46.6337 mg/m used as an estimate of lethality 10 threshold in female rats. 11 12 Time scaling: Cn x t = k, where n = 4.8 13 14 Uncertainty factors: Total uncertainty factor adjustment is 30. 15 Interspecies: 3: Variability is primarily a function of varying 16 cholinesterase activity levels and types of cholinesterase present; 17 humans have greater levels of plasma cholinesterase with which to 18 bind anticholinesterases such as fenamiphos than do other species. 19 This decreases the dose to critical targets. Therefore, the interspecies 20 uncertainty factor is limited to 3. 21 Intraspecies: 10: The documented variability in sensitivity among 22 different age groups and genders, and the known genetic 23 polymorphisms in A-esterases justify retention of the intraspecies 24 uncertainty factor of 10. 25 26 Modifying factor: None 27 28 Calculation: 46.6337 mg/m3/ 30 = 1.5545 mg/m3 29 C4.8 x t = k 30 (1.5545 mg/m3)4.8 x 240 min = 1994.558 mg/m3(4.8)·min 31 32 10-minute AEGL-3 C4. 8 x 10 min = 1994.558 mg/m3(4.8)·min 33 C= 3.0 mg/m3 34 35 30-minute AEGL-3 C4. 8 x 30 min = 1994.558 mg/m3(4.8)·min 36 C= 2.4 mg/m3 37 38 1-hour AEGL-3 C4. 8 x 60 min = 1994.558 mg/m3(4.8)·min 39 C = 2.1 mg/m3 40 41 4-hour AEGL-3 C4. 8 x 240 min = 1994.558 mg/m3(4.8)·min 42 C = 1.6 mg/m3 43 44 8-hour AEGL-3 C4. 8 x 480 min = 1994.558 mg/m3(4.8)·min 45 C = 1.3 mg/m3 46

28 FENAMIPHOS PROPOSED: November 2009

1 APPENDIX B: Time-Scaling Calculations 2 3 The relationship between dose and time for any given chemical is a function of the 4 physical and chemical properties of the substance and the unique toxicological and 5 pharmacological properties of the individual substance. Historically, the relationship according 6 to Haber (1924), commonly called Haber=s Law or Haber=s Rule (i.e., C x t = k, where C = 7 exposure concentration, t = exposure duration, and k = a constant) has been used to relate 8 exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states 9 that exposure concentration and exposure duration may be reciprocally adjusted to maintain a 10 cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a 11 specific quantitative and qualitative response. This inverse relationship of concentration and 12 time may be valid when the toxic response to a chemical is equally dependent upon the 13 concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of 14 LC50 data for certain chemicals revealed chemical-specific relationships between exposure 15 concentration and exposure duration that were often exponential. This relationship can be 16 expressed by the equation C n x t = k, where n represents a chemical specific, and even a toxic 17 endpoint specific, exponent. The relationship described by this equation is basically in the form 18 of a linear regression analysis of the log-log transformation of a plot of C vs. ten Berge et al. 19 (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship 20 relative to death for approximately 20 chemicals and found that the empirically derived value of 21 n ranged from 0.8 to 3.5 among this group of chemicals. Hence, the value of the exponent (n) in 22 the equation Cn x t = k quantitatively defines the relationship between exposure concentration 23 and exposure duration for a given chemical and for a specific health effect endpoint. Haber's 24 Rule is the special case where n = 1. As the value of n increases, the plot of concentration vs. 25 time yields a progressive decrease in the slope of the curve. 26 27 Filename: Fenamiphos Rat for Log Probit Model 28 Date: 29 June 2009 Time: 13:55:58 29 30 Used Probit Equation Y = B0 + B1*X1 + B2*X2 31 X1 = conc ppm, ln-transformed 32 X2 = minutes, ln-transformed 33 34 ChiSquare = 85.89 35 Degrees of freedom = 32 36 Probability Model = 8.05E-07 37 38 Ln(Likelihood) = -70.87 39 40 B 0 = -6.0550E+00 Student t = -3.2592 41 B 1 = 3.4435E+00 Student t = 7.7738 42 B 2 = 7.2006E-01 Student t = 2.6363 43 44 variance B 0 0 = 3.4514E+00 45 covariance B 0 1 = -6.7025E-01 46 covariance B 0 2 = -4.3645E-01 47 variance B 1 1 = 1.9621E-01 48 covariance B 1 2 = 4.9704E-02 29 FENAMIPHOS PROPOSED: November 2009

1 variance B 2 2 = 7.4601E-02 2 3 Estimation ratio between regression coefficients of ln(conc) and ln(minutes) 4 Point estimate = 4.782 5 Lower limit (95% CL) = 1.415 6 Upper limit (95% CL) = 8.150 7 8

30 FENAMIPHOS PROPOSED: November 2009

1 2 3 APPENDIX C: Derivation Summary for Fenamiphos AEGLs 4 5 ACUTE EXPOSURE GUIDELINE LEVELS FOR 6 FENAMIPHOS (CAS Reg. No. 22224-92-6) 7 DERIVATION SUMMARY 8 AEGL-1 VALUES 10-minute 30-minute 1-hour 4-hour 8-hour NR NR NR NR NR Key Reference: NA Test Species/Strain/Number: NA Exposure Route/Concentrations/Duration: NA Effects: NA Endpoint/Concentration/Rationale: NA Uncertainty Factors/Rationale: NA Modifying Factor: NA Animal to Human Dosimetric Adjustment: NA Time Scaling: NA Data Adequacy: No AEGL-1 values were established because the AEGL-1 values would have been too close to or exceeded AEGL-2 values. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 9

31 FENAMIPHOS PROPOSED: November 2009

1 AEGL-2 VALUES 10-minute 30-minute 1-hour 4-hour 8-hour 1.0 mg/m3 0.80 mg/m3 0.70 mg/m3 0.53 mg/m3 0.43 mg/m3 Key Reference: Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no. 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany. Test Species/Strain/Number: NA Exposure Route/Concentrations/Durations: One-third the AEGL-3 values. Supported by steep concentration- response curve. Male rats experienced 5% mortality after exposure to 75 mg/m3 for 1 hour; 30% mortality at 87 mg/m3; and 60% mortality at 103 mg/m3. All 20 rats died after exposure to 187 mg/m3 (Kimmerle 1972). In a study by Thyssen (1979a), 20% of the male rats died after exposure to 119 mg/m3 for 1 hour; 60% died after exposure to 145 mg/m3; and 90% died after exposure to 148 mg/m3. Female rats had 70% mortality at 145 mg/m3 and 90% mortality after exposure to 148 mg/m3 for 1 hour. In a 4-hour study by Thyssen (1979a), male rats experienced 60% mortality at 100 mg/m3 and 100% mortality at 155 mg/m3, and female rats experienced 50% mortality at 100 mg/m3; 90% mortality at 155 mg/m3; and 100% mortality at 191 mg/m3. Effects: NA Endpoint/Concentration/Rationale: One-third the AEGL-3 values. Uncertainty Factors/Rationale: NA Modifying Factor: NA Animal to Human Dosimetric Adjustment: NA Time Scaling:NA Data Adequacy: Data were not available on AEGL-2 tier effects. 2

32 FENAMIPHOS PROPOSED: November 2009

1 2 AEGL-3 VALUES 10-minute 30-minute 1-hour 4-hour 8-hour 3.0 mg/m3 2.4 mg/m3 2.1 mg/m3 1.6 mg/m3 1.3 mg/m3 Key Reference: Thyssen, J. 1979a. SRA 3886 (Nemacur active ingredient) acute inhalational toxicity studies. Report no. 8210. Unpublished study prepared by Bayer AG, Institut fuer Toxikologie, Germany. Test Species/Strain/Number: Female Rat/TNO/W74 / 10/group Exposure Route/Concentrations/Duration: Inhalation/ 57, 62, 100, 155, 191 mg/m3/240 min Effects: 57 mg/m3 Cholinesterase activity inhibition 62 mg/m3 10% mortality; (1/10) 100 mg/m3 50% mortality, (5/10) 155 mg/m3 90% mortality; (9/10) 191 mg/m3 100% mortality; (10/10) 3 Endpoint/Concentration/Rationale: Estimated threshold of lethality, BMCL05 of 46.6337 mg/m Uncertainty Factors/Rationale: Total uncertainty factor adjustment is 30 Interspecies: 3: Variability is primarily a function of varying cholinesterase activity levels and types of cholinesterase present; humans have greater levels of plasma cholinesterase with which to bind antichlolinesterase agents such as fenamiphos than do other species. Intraspecies: 10: The documented variability in sensitivity among different age groups and genders, and the known genetic polymorphisms in A-esterases justify retention of the intraspecies uncertainty factor of 10. Modifying Factor: none applied Animal to Human Dosimetric Adjustment: NA Time Scaling: Cn x t = k, where n = 4.8 Data Adequacy: Data are limited to one species but consistent and adequate for AEGL-3 derivation.

3 4

33 FENAMIPHOS PROPOSED: November 2009

1 2 APPENDIX D: Category Plot for Fenamiphos Chemical Toxicity - TSD Data Fenamiphos 1000

100 No Effect

Discomfort

10 Disabling ppm

Some Lethal

AEGL-3 Lethal 1

AEGL-2 AEGL

0 0 60 120 180 240 300 360 420 480 3 Minutes

34 FENAMIPHOS PROPOSED: November 2009

1 For Category 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species Sex # Exposures Mg/m3 Minutes Category Comments

NAC/AEGL-1 NR 10 AEGL NAC/AEGL-1 NR 30 AEGL NAC/AEGL-1 NR 60 AEGL NAC/AEGL-1 NR 240 AEGL NAC/AEGL-1 NR 480 AEGL

NAC/AEGL-2 1.0 10 AEGL NAC/AEGL-2 0.80 30 AEGL NAC/AEGL-2 0.70 60 AEGL NAC/AEGL-2 0.53 240 AEGL NAC/AEGL-2 0.43 480 AEGL

NAC/AEGL-3 3.0 10 AEGL NAC/AEGL-3 2.4 30 AEGL NAC/AEGL-3 2.1 60 AEGL NAC/AEGL-3 1.6 240 AEGL NAC/AEGL-3 1.3 480 AEGL Kimmerle 1972 rat m 1 29 60 0 No effect Kimmerle 1972 rat m 1 75 60 SL 5% mortality Kimmerle 1972 rat m 1 87 60 SL 30% mortality Kimmerle 1972 rat m 1 103 60 SL 60% mortality Kimmerle 1972 rat m 1 140 60 SL 65% mortality Kimmerle 1972 rat m 1 165 60 SL 95% mortality Kimmerle 1972 rat m 1 187 60 3 100% mortality Kimmerle 1972 rat f 1 29 60.0 0 No effect Kimmerle 1972 rat f 1 70 60.0 1 Cholinesterase activity inhibition Kimmerle 1972 rat f 1 105 60 SL 5% mortality Kimmerle 1972 rat f 1 117 60 1 Cholinesterase activity inhibition Kimmerle 1972 rat f 1 148 60 SL 35% mortality Kimmerle 1972 rat f 1 170 60 SL 60% mortality Kimmerle 1972 rat f 1 185 60 SL 90% mortality Kimmerle 1972 rat f 1 195 60 SL 90% mortality Kimmerle 1972 rat f 1 320 60 3 100% mortality Thyssen 1979 a rat m 1 83 60 1 Cholinesterase activity inhibition Thyssen 1979 a rat m 1 119 60 SL 20% mortality Thyssen 1979 a rat m 1 145 60 SL 60% mortality Thyssen 1979 a rat m 1 148 60 SL 90% mortality Thyssen 1979 a rat m 1 250 60 3 100% mortality Thyssen 1979 a rat f 1 83 60 1 Cholinesterase activity inhibition Thyssen 1979 a rat f 1 119 60 1 Cholinesterase activity

35 FENAMIPHOS PROPOSED: November 2009

inhibition Thyssen 1979 a rat f 1 145 60 SL 70% mortality Thyssen 1979 a rat f 1 148 60 SL 90% mortality Thyssen 1979 a rat f 1 250 60 3 100% mortality Thyssen 1979 a rat m 1 57 240 1 Cholinesterase activity inhibition Thyssen 1979 a rat m 1 62 240 1 Cholinesterase activity inhibition Thyssen 1979 a rat m 1 100 240 SL 60% mortality Thyssen 1979 a rat m 1 155 240 3 100% mortality Thyssen 1979 a rat f 1 57 240 1 Cholinesterase activity inhibition Thyssen 1979 a rat f 1 62 240 SL 10% mortality Thyssen 1979 a rat f 1 100 240 SL 50% mortality Thyssen 1979 a rat f 1 155 240 SL 90% mortality Thyssen 1979 a rat f 1 191 240 3 100% mortality 1 NR: Not Recommended. Absence of AEGL-1 values does not imply that concentrations below the AEGL-2 are without effect. 2

36 FENAMIPHOS PROPOSED: November 2009

1 APPENDIX E: Benchmark Exposure Calculations 2 3 Kimmerle 1972, Male rat BMC01 & BMCL05 4 ======5 BMDS Model Run 6 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 7 The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 8 where CumNorm(.) is the cumulative normal distribution function 9 10 Dependent variable = Incidence 11 Independent variable = DOSE 12 Slope parameter is restricted as slope >= 1 13 Total number of observations = 8 14 Total number of records with missing values = 0 15 Maximum number of iterations = 250 16 Relative Function Convergence has been set to: 1e-008 17 Parameter Convergence has been set to: 1e-008 18 19 User has chosen the log transformed model 20 21 Default Initial (and Specified) Parameter Values 22 background = 0 23 intercept = -9.96579 24 slope = 2.17922 25 26 Asymptotic Correlation Matrix of Parameter Estimates 27 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, 28 and do not appear in the correlation matrix ) 29 30 intercept slope 31 intercept 1 -1 32 slope -1 1 33 34 Parameter Estimates 35 95.0% Wald Confidence Interval 36 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 37 background 0 NA 38 intercept -15.5684 2.36683 -20.2073 -10.9295 39 slope 3.33473 0.502325 2.35019 4.31926 40 41 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 42 43 Analysis of Deviance Table 44 Model Log(likelihood) # Param's Deviance Test d.f. P-value 45 Full model -46.5671 8 46 Fitted model -50.4366 2 7.73902 6 0.2579 47 Reduced model -109.889 1 126.644 7 <.0001 48 AIC: 104.873 49 50 Goodness of Fit 51 Scaled 52 Dose Est._Prob. Expected Observed Size Residual 53 ------54 0.0000 0.0000 0.000 0.000 20 0.000 55 29.0000 0.0000 0.000 0.000 20 -0.012 56 75.0000 0.1209 2.417 1.000 20 -0.972 57 87.0000 0.2496 4.992 6.000 20 0.521 58 103.0000 0.4551 9.102 12.000 20 1.301 59 140.0000 0.8188 16.375 13.000 20 -1.959 60 165.0000 0.9277 18.553 19.000 20 0.386 61 187.0000 0.9697 19.393 20.000 20 0.791 62 Chi^2 = 7.52 d.f. = 6 P-value = 0.2752

37 FENAMIPHOS PROPOSED: November 2009

1 2 Benchmark Dose Computation 3 Specified effect = 0.05 0.01 4 Risk Type = Extra risk Extra risk 5 Confidence level = 0.95 0.95 6 BMC = 65.0603 53.035 7 BMCL = 54.181 41.6366 8 LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 dose 9 10:48 09/28 2009 10 BMCL05 graph 11

38 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 dose 1 10:53 09/28 2009 2 3 BMC01 graph 4 5 6 Kimmerle 1972, Female rat BMC01 & BMCL05 7 ======8 BMDS Model Run 9 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 10 The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 11 where CumNorm(.) is the cumulative normal distribution function 12 13 Dependent variable = Incidence 14 Independent variable = DOSE 15 Slope parameter is restricted as slope >= 1 16 Total number of observations = 10 17 Total number of records with missing values = 0 18 Maximum number of iterations = 250 19 Relative Function Convergence has been set to: 1e-008 20 Parameter Convergence has been set to: 1e-008 21 22 User has chosen the log transformed model 23 24 Default Initial (and Specified) Parameter Values 25 background = 0 26 intercept = -9.31195 27 slope = 1.86448 28 29 Asymptotic Correlation Matrix of Parameter Estimates

39 FENAMIPHOS PROPOSED: November 2009

1 background intercept slope 2 background 1 -0.14 0.14 3 intercept -0.14 1 -1 4 slope 0.14 -1 1 5 6 Parameter Estimates 7 95.0% Wald Confidence Interval 8 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 9 background 0.0198728 0.0144703 -0.00848849 0.048234 10 intercept -36.2316 7.26212 -50.465 -21.9981 11 slope 7.13557 1.41567 4.36092 9.91023 12 13 Analysis of Deviance Table 14 Model Log(likelihood) # Param's Deviance Test d.f. P-value 15 Full model -47.3531 10 16 Fitted model -50.0328 3 5.35949 7 0.6162 17 Reduced model -133.292 1 171.877 9 <.0001 18 AIC: 106.066 19 20 Goodness of Fit 21 Scaled 22 Dose Est._Prob. Expected Observed Size Residual 23 ------24 0.0000 0.0199 0.397 0.000 20 -0.637 25 29.0000 0.0199 0.397 0.000 20 -0.637 26 70.0000 0.0199 0.397 1.000 20 0.965 27 105.0000 0.0211 0.422 1.000 20 0.899 28 117.0000 0.0318 0.637 0.000 20 -0.811 29 148.0000 0.2974 5.948 7.000 20 0.515 30 170.0000 0.6678 13.356 12.000 20 -0.644 31 185.0000 0.8489 16.978 18.000 20 0.638 32 195.0000 0.9200 18.400 18.000 20 -0.330 33 320.0000 1.0000 20.000 20.000 20 0.003 34 Chi^2 = 4.40 d.f. = 7 P-value = 0.7321 35 36 Benchmark Dose Computation 37 Specified effect = 0.05 0.01 38 Risk Type = Extra risk Extra risk 39 Confidence level = 0.95 0.95 40 BMC = 127.368 115.766 41 BMCL = 112.538 98.4546 42 43

40 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 250 300 dose 1 11:02 09/28 2009 2 3 BMCL05 graph

41 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 250 300 dose 1 11:02 09/28 2009 2 BMC01 graph 3 4 5 Thyssen 1979a, Male rat BMC01 & BMCL05 (1-hr exposure) 6 ======7 BMDS Model Run 8 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9 The form of the probability function is: P[response] = Background + (1-Background) * CumNorm Intercept+ Slope* 10 Log(Dose)),where CumNorm(.) is the cumulative normal distribution function 11 12 Dependent variable = Incidence 13 Independent variable = DOSE 14 Slope parameter is restricted as slope >= 1 15 Total number of observations = 6 16 Total number of records with missing values = 1 17 Maximum number of iterations = 250 18 Relative Function Convergence has been set to: 1e-008 19 Parameter Convergence has been set to: 1e-008 20 21 User has chosen the log transformed model 22 23 Default Initial (and Specified) Parameter Values 24 background = 0 25 intercept = -21.4189 26 slope = 4.41679 27 28 Asymptotic Correlation Matrix of Parameter Estimates

42 FENAMIPHOS PROPOSED: November 2009

1 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, 2 and do not appear in the correlation matrix ) 3 4 intercept slope 5 intercept 1 -1 6 slope -1 1 7 8 Parameter Estimates 9 95.0% Wald Confidence Interval 10 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 11 background 0 NA 12 intercept -37.4632 12.8407 -62.6304 -12.2959 13 slope 7.65312 2.60905 2.53947 12.7668 14 15 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 16 17 Analysis of Deviance Table 18 Model Log(likelihood) # Param's Deviance Test d.f. P-value 19 Full model -14.985 5 20 Fitted model -15.8938 2 1.81769 3 0.6111 21 Reduced model -32.0518 1 34.1336 4 <.0001 22 AIC: 35.7876 23 24 Goodness of Fit 25 Scaled 26 Dose Est._Prob. Expected Observed Size Residual 27 ------28 0.0000 0.0000 0.000 0.000 10 0.000 29 83.0000 0.0001 0.001 0.000 10 -0.037 30 119.0000 0.1873 1.873 2.000 10 0.103 31 145.0000 0.7338 7.338 6.000 10 -0.957 32 148.0000 0.7826 7.826 9.000 10 0.900 33 Chi^2 = 1.74 d.f. = 3 P-value = 0.6284 34 35 Benchmark Dose Computation 36 Specified effect = 0.05 0.01 37 Risk Type = Extra risk Extra risk 38 Confidence level = 0.95 0.95 39 BMC = 107.795 98.6107 40 BMCL = 86.1218 72.8367 41

43 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 20 40 60 80 100 120 140 dose 1 11:12 09/28 2009 2 Male BMCL05 graph 3 4

44 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 20 40 60 80 100 120 140 dose 1 11:11 09/28 2009 2 Male BMC01 graph 3 4 Thyssen 1979a, Female rat BMC01 & BMCL05 (1-hr exposure) 5 ======6 BMDS Model Run 7 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 8 The form of the probability function is: P[response] = Background+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 9 where CumNorm(.) is the cumulative normal distribution function 10 11 Dependent variable = Incidence 12 Independent variable = DOSE 13 Slope parameter is restricted as slope >= 1 14 Total number of observations = 6 15 Total number of records with missing values = 0 16 Maximum number of iterations = 250 17 Relative Function Convergence has been set to: 1e-008 18 Parameter Convergence has been set to: 1e-008 19 20 User has chosen the log transformed model 21 22 Default Initial (and Specified) Parameter Values 23 background = 0 24 intercept = -17.1708 25 slope = 3.48147 26 27 Asymptotic Correlation Matrix of Parameter Estimates 28 ( *** The model parameter(s) -background -slope have been estimated at a boundary point, or have been specified by the user, 29 and do not appear in the correlation matrix )

45 FENAMIPHOS PROPOSED: November 2009

1 intercept 2 intercept 1 3 4 Parameter Estimates 5 95.0% Wald Confidence Interval 6 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 7 background 0 NA 8 intercept -88.909 0.320323 -89.5369 -88.2812 9 slope 18 NA 10 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 11 12 Analysis of Deviance Table 13 Model Log(likelihood) # Param's Deviance Test d.f. P-value 14 Full model -9.35947 6 15 Fitted model -9.54616 1 0.373373 5 0.996 16 Reduced model -41.0539 1 63.3889 5 <.0001 17 AIC: 21.0923 18 19 Goodness of Fit 20 Scaled 21 Dose Est._Prob. Expected Observed Size Residual 22 ------23 0.0000 0.0000 0.000 0.000 10 0.000 24 83.0000 0.0000 0.000 0.000 10 -0.000 25 119.0000 0.0020 0.020 0.000 10 -0.140 26 145.0000 0.7493 7.493 7.000 10 -0.359 27 148.0000 0.8510 8.510 9.000 10 0.435 28 250.0000 1.0000 10.000 10.000 10 0.000 29 Chi^2 = 0.34 d.f. = 5 P-value = 0.9969 30 31 Benchmark Dose Computation 32 Specified effect = 0.05 0.01 33 Risk Type = Extra risk Extra risk 34 Confidence level = 0.95 0.95 35 BMC = 127.487 122.75 36 BMCL = 113.898 106.19 37 38 39

46 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 250 dose 1 11:13 09/28 2009 2 Female BMCL05 graph 3

47 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 250 dose 1 11:17 09/28 2009 2 Female BMC01 graph 3 4 Thyssen 1979a, Male BMC01 & BMCL05 (4-hr exposure) 5 ======6 BMDS Model Run 7 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 8 The form of the probability function is: P[response] = Background+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 9 where CumNorm(.) is the cumulative normal distribution function 10 11 Dependent variable = Incidence 12 Independent variable = DOSE 13 Slope parameter is restricted as slope >= 1 14 Total number of observations = 5 15 Total number of records with missing values = 0 16 Maximum number of iterations = 250 17 Relative Function Convergence has been set to: 1e-008 18 Parameter Convergence has been set to: 1e-008 19 20 User has chosen the log transformed model 21 22 Default Initial (and Specified) Parameter Values 23 background = 0 24 intercept = -16.1037 25 slope = 3.53434 26 27 Asymptotic Correlation Matrix of Parameter Estimates 28 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, 29 and do not appear in the correlation matrix )

48 FENAMIPHOS PROPOSED: November 2009

1 intercept slope 2 intercept 1 -1 3 slope -1 1 4 5 Parameter Estimates 6 95.0% Wald Confidence Interval 7 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 8 background 0 NA 9 intercept -58.192 6825.98 -13436.9 13320.5 10 slope 12.6913 1482.24 -2892.45 2917.84 11 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 12 13 Analysis of Deviance Table 14 Model Log(likelihood) # Param's Deviance Test d.f. P-value 15 Full model -6.73012 5 16 Fitted model -6.73012 2 1.21757e-007 3 1 17 Reduced model -31.3435 1 49.2267 4 <.0001 18 AIC: 17.4602 19 20 Goodness of Fit 21 Scaled 22 Dose Est._Prob. Expected Observed Size Residual 23 ------24 0.0000 0.0000 0.000 0.000 10 0.000 25 57.0000 0.0000 0.000 0.000 10 -0.000 26 62.0000 0.0000 0.000 0.000 10 -0.000 27 100.0000 0.6000 6.000 6.000 10 0.000 28 155.0000 1.0000 10.000 10.000 10 0.000 29 Chi^2 = 0.00 d.f. = 3 P-value = 1.0000 30 31 Benchmark Dose Computation 32 Specified effect = 0.05 0.01 33 Risk Type = Extra risk Extra risk 34 Confidence level = 0.95 0.95 35 BMC = 86.108 81.6062 36 BMCL = 59.2137 49.4938 37 38

49 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 20 40 60 80 100 120 140 160 dose 1 11:35 09/28 2009 2 Male BMCL05 graph

50 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 20 40 60 80 100 120 140 160 dose 1 11:38 09/28 2009 2 Male BMC01 graph 3 4 5 Thyssen 1979a, Female BMC01 & BMCL05 (4-hr exposure) 6 ======7 BMDS Model Run 8 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9 The form of the probability function is: P[response] = Background+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 10 where CumNorm(.) is the cumulative normal distribution function 11 12 Dependent variable = Incidence 13 Independent variable = DOSE 14 Slope parameter is restricted as slope >= 1 15 Total number of observations = 6 16 Total number of records with missing values = 0 17 Maximum number of iterations = 250 18 Relative Function Convergence has been set to: 1e-008 19 Parameter Convergence has been set to: 1e-008 20 21 User has chosen the log transformed model 22 23 Default Initial (and Specified) Parameter Values 24 background = 0 25 intercept = -12.8595 26 slope = 2.78692 27 28 Asymptotic Correlation Matrix of Parameter Estimates

51 FENAMIPHOS PROPOSED: November 2009

1 ( *** The model parameter(s) -background have been estimated at a boundary point, or have been specified by the user, 2 and do not appear in the correlation matrix ) 3 4 intercept slope 5 intercept 1 -1 6 slope -1 1 7 8 Parameter Estimates 9 95.0% Wald Confidence Interval 10 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 11 background 0 NA 12 intercept -15.2331 3.24344 -21.5901 -8.87605 13 slope 3.30866 0.704182 1.92849 4.68883 14 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. 15 16 Analysis of Deviance Table 17 Model Log(likelihood) # Param's Deviance Test d.f. P-value 18 Full model -13.4331 6 19 Fitted model -14.1051 2 1.34385 4 0.8539 20 Reduced model -40.7516 1 54.6369 5 <.0001 21 AIC: 32.2101 22 23 Goodness of Fit 24 Scaled 25 Dose Est._Prob. Expected Observed Size Residual 26 ------27 0.0000 0.0000 0.000 0.000 10 0.000 28 57.0000 0.0317 0.317 0.000 10 -0.572 29 62.0000 0.0573 0.573 1.000 10 0.581 30 100.0000 0.5015 5.015 5.000 10 -0.010 31 155.0000 0.9270 9.270 9.000 10 -0.328 32 191.0000 0.9840 9.840 10.000 10 0.403 33 Chi^2 = 0.94 d.f. = 4 P-value = 0.9194 34 35 Benchmark Dose Computation 36 Specified effect = 0.05 0.01 37 Risk Type = Extra risk Extra Risk 38 Confidence level = 0.95 0.95 39 BMC = 60.7558 49.4464 40 BMCL = 46.6337 34.904 41 42 43 44 45

52 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 dose 1 11:43 09/28 2009 2 Female BMCL05 graph 3

53 FENAMIPHOS PROPOSED: November 2009

LogProbit Model with 0.95 Confidence Level

LogProbit 1

0.8

0.6

0.4 Fraction Affected

0.2

0 BMDL BMD 0 50 100 150 200 dose 1 11:45 09/28 2009 2 3 Female BMC01 graph 4 5